Synthesis and Characterization of 4,11-Diaminoanthra[2,3-b]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD(+)/NADH Ratio and SIRT1

  • J Med Chem. 2015 Dec 24;58(24):9522-34. doi: 10.1021/acs.jmedchem.5b00859.
Alexander S Tikhomirov  1  2 ,  Andrey E Shchekotikhin  1  2 ,  Yi-Hui Lee  3 ,  Yi-Ann Chen  3 ,  Chia-An Yeh  3 ,  Victor V Tatarskiy Jr  4 ,  Lyubov G Dezhenkova  1 ,  Valeria A Glazunova  4 ,  Jan Balzarini  5 ,  Alexander A Shtil  4  6 ,  Maria N Preobrazhenskaya  1 ,  Pin Ju Chueh  3  7  8  9
Affiliations
  • 1. Gause Institute of New Antibiotics , 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
  • 2. Mendeleyev University of Chemical Technology , 9 Miusskaya Square, Moscow 125190, Russia.
  • 3. Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan.
  • 4. Blokhin Cancer Center , 24 Kashirskoye Shosse, Moscow 115478, Russia.
  • 5. Rega Institute for Medical Research, Katholieke Universiteit Leuven , 3000 Leuven, Belgium.
  • 6. National University of Science and Technology "MISIS", 4 Leninsky Avenue, Moscow 119991, Russia.
  • 7. Graduate Institute of Basic Medicine, China Medical University , Taichung 40402, Taiwan.
  • 8. Department of Medical Research, China Medical University Hospital , Taichung 40402, Taiwan.
  • 9. Department of Biotechnology, Asia University , Taichung 41354, Taiwan.
PMID: 26633734 DOI: 10.1021/acs.jmedchem.5b00859
Abstract

A series of new 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives with different side chains were synthesized. Selected 2-unsubstituted derivatives 11-14 showed high antiproliferative potency on a panel of mammalian tumor cell lines including multidrug resistance variants. Compounds 11-14 utilized multiple mechanisms of cytotoxicity including inhibition of Top1/Top2-mediated DNA relaxation, reduced NAD(+)/NADH ratio through tNOX inhibition, suppression of a NAD(+)-dependent Sirtuin 1 (SIRT1) deacetylase activity, and activation of caspase-mediated Apoptosis. Here, for the first time, we report that tumor-associated NADH oxidase (tNOX) and SIRT1 are important cellular targets of antitumor anthracene-9,10-diones.